A phase I evaluation of intravenous (IV) 131I-chlorotoxin delivery to solid peripheral and intracranial tumors

Abstract

e14507 Background: Pre-clinical studies demonstrate TM601 binding to glioblastoma, melanoma, and other tumor types in vitro and in vivo (human xenograft tumors in mice). Here we report imaging and safety data from a Phase I clinical trial in patients with recurrent metastatic somatic and/or cerebral solid tumors that received IV 131I-TM601. Methods: Patients received an IV imaging test dose of 10 mCi/0.2mg 131I-TM601. Subjects not showing tumor localization, received a second imaging test dose of 20 mC/0.4mg 131I-TM601. Subjects without localization at either dose were dropped from study; patients showing tumor localization without toxicity then received a 30 mCi/0.6mg 131I-TM601 IV injection. The primary objectives were to: 1) determine whole body localization and dosimetry, 2) estimate the maximum tolerated dose based on normal tissue dosimetry and 3) determine the acute toxicity of IV 131I-TM601. Results: A total of 44 evaluable patients received IV doses of 131I-TM601 without dose-limiting toxicity. 31/44 (70%) showed tumor specific uptake on follow-up gamma camera or SPECT imaging. Tumor-specific uptake was observed in patients with malignant glioma (7/8), metastatic melanoma (7/7), non-small cell lung cancer (3/4), colon cancer (6/7), pancreatic cancer (2/3), prostate cancer (2/2), breast cancer (1/4) and in one evaluable patient each with transitional cell carcinoma, pleomorphic xanthoastrocytoma and metastatic paraganglioma. Notably, all patients with metastatic cerebral disease showed tumor-specific uptake of systemically injected 131I-TM601. No uptake was seen in CNS lymphoma (n=1), ovarian (n=2), small cell lung (n=2), or medulllary thyroid cancers (n=1). Conclusions: Tumor-specific uptake of IV 131I-TM601 in primary and metastatic (including brain) solid tumors suggests that further dose escalation is warranted. Notably, IV injected 131I-TM601 crossed the blood brain barrier. Based on normal tissue dosimetry from this study, future clinical trials will evaluate safety and therapeutic efficacy in patients with recurrent glioma and metastatic melanoma at doses up to 100 mCi 131I-TM601 (maximum single dose). [Table: see text]